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| United States Patent |
5,792,474
|
|
Rauchfuss
|
August 11, 1998
|
Process for the production of retarded pharmaceutical compositions
Abstract
According to the present invention, there is provided a continuous method
for the production of retarded pharmaceutical compositions by an extrusion
process. A mixture of an active material, a low and high melting lipid or
lipoid components is introduced by means of an extruder screw conveyor
into a preheated extruder and brought to a temperature which is at most
about 4.degree. C. above the melting temperature of the low melting
component at a pressure of about 200 to about 600 kPa(N/m.sup.2). The mass
is extruded through a nozzle plate with a nozzle diameter of about 1.2 to
about 4 mm and subsequently cooled, and if desired, granulated.
| Inventors:
|
Rauchfuss; Roland (Freiburg, DE)
|
| Assignee:
|
Goedecke Aktiengesellschaft (Berlin, DE)
|
| Appl. No.:
|
362592 |
| Filed:
|
June 16, 1995 |
| PCT Filed:
|
May 21, 1993
|
| PCT NO:
|
PCT/EP93/01289
|
| 371 Date:
|
June 16, 1995
|
| 102(e) Date:
|
June 16, 1995
|
| PCT PUB.NO.:
|
WO93/24110 |
| PCT PUB. Date:
|
December 9, 1993 |
Foreign Application Priority Data
| May 22, 1992[DE] | 42 16 948.8 |
| Current U.S. Class: |
424/489; 424/449; 424/468; 424/470; 424/490; 424/491 |
| Intern'l Class: |
A61K 009/14 |
| Field of Search: |
424/470,489,490,488,449,452
|
References Cited
U.S. Patent Documents
| 4483847 | Nov., 1984 | Augart | 424/22.
|
| 4540602 | Sep., 1985 | Motoyama et al. | 424/34.
|
| 5518730 | May., 1996 | Fuisz | 424/426.
|
| Foreign Patent Documents |
| 204596 | May., 1986 | EP | .
|
Primary Examiner: Phelan; D. Gabrielle
Assistant Examiner: Benston, Jr.; William E.
Attorney, Agent or Firm: Atkins; Michael J.
Claims
What is claimed is:
1. Process for the production of a pharmaceutical composition with retarded
liberation of active material comprising the steps of:
(a) mixing the active material not only with a high melting lipid or lipoid
component but also with a low melting lipid or lipoid component, the
weight ratio of the two lipid or lipoid components being in the range of
about 1:5 to about 5:1;
(b) introducing the resulting mixture by means of an extruded screw
conveyor into a preheated extruded;
(c) bringing the resulting mixture of active material and lipid or lipoid
components to a temperature which lies above the melting point of the low
melting component but below the melting point of the high melting
component, the temperature being at most 40 C above the melting
temperature of the low melting component, the so heated mixture being
subject to a pressure of about 200 to about 600 kPa(Nm.sup.2), the active
material and the high melting component thereby being uniformly dispersed
in the completely molten low melting component and extruded through a
nozzle plate with a nozzle diameter of about 1.2 to about 4 mm;
(d) allowing the resulting mixture, after melting of the low melting
component to cool to below the melting point thereof, and
(e) granulating the resulting mixture during the cooling or thereafter.
2. Process according to claim 1 wherein the diameter of the screw conveyor
is about 50 mm.
3. Process according to claim 1, wherein the temperature according to (d)
is a working temperature of about 58.degree. to about 60.degree. C.
4. Process for the production of a pharmaceutical composition with retarded
liberation of active material comprising the steps of:
(a) mixing the active material not only with a high melting lipid or lipoid
component but also with a low melting lipid or lipoid component, the
weight ratio of the two lipid or lipoid components being in the range of
about 1:5 to about 5:1;
(b) introducing the resulting mixture by means of an extruder screw
conveyor into a preheated extruder;
(c) bringing the resulting mixture of active material and lipid or lipoid
components to a temperature which lies above the melting point of the low
melting component but below the melting point of the high melting
component, the temperature being about 1 to about 30 C above the melting
temperature of the low melting component, the so heated mixture being
subjected to a pressure of about 200 to about 600 kPa (N/m.sup.2), the
active material and the high melting component thereby being uniformly
dispersed in the completely molten low melting and extruded through a
nozzle plate with a nozzle diameter of about 1.3 to about 3 mm;
(d) allowing the resulting mixture, after melting of the low melting
component to cool to below the melting point thereof; and
(e) granulating the resulting mixture during the cooling or thereafter.
5. Process according to claim 4, wherein the temperature according to (d)
is about 1.degree. to about 2.degree. C. above the melting temperature of
the low melting lipid or lipoid component.
6. Process according to claim 4, wherein the nozzle diameter in the nozzle
plates is about 1.5 to about 2 mm.
7. Process according to claim 4, wherein the speed of rotation for the
extruder is in the range from about 170 to about 180 rpm.
8. Process according to claim 4, wherein the screw conveyor length is about
1200 mm.
9. Process according to claim 4, wherein the diameter of the screw conveyor
is about 50 mm.
10. Process according to claim 4, wherein the temperature according to (d)
is a working temperature of about 58.degree. to about 60.degree. C.
11. Process for the production of a pharmaceutical composition with
retarded liberation of active material comprising the steps of:
(a) mixing the active material not only with a high melting lipid or lipoid
component but also with a low melting lipid or lipoid component, the
weight ratio of the two lipid or lipoid components being in the range of
about 1:5 to about 5:1;
(b) introducing the resulting mixture by means of an extruder screw
conveyor into a preheated extruder;
(c) bringing the resulting mixture of active material and lipid or lipoid
components to a temperature which lies above the melting point of the low
melting component but below the melting point of the high melting
component, the temperature being at most about 1 to about 20 C above the
melting temperature of the low melting component, the so heated mixture
being subjected to a pressure of about 200 to about 600 kPa (N/m.sup.2),
the active material and the high melting component thereby being uniformly
dispersed in the completely molten low melting and extruded through a
nozzle plate with a nozzle diameter of 1.5 to 2 mm;
(d) allowing the resulting mixture, after melting of the low melting
component to cool to below the melting point thereof; and
(e) granulating the resulting mixture during the cooling or thereafter.
12. Process according to claim 11, wherein the speed of rotation for the
extruder is in the range from about 170 to about 180 rpm.
13. Process according to claim 12, wherein the screw conveyor length is
about 1200 mm.
14. Process according to claim 13, wherein the diameter of the screw
conveyor is about 50 mm.
15. Process according to claim 14, wherein the temperature according to (d)
is a working temperature of about 58.degree. to about 60.degree. C.
Description
This application is a 371 of PCT/EP93/01289 filed May 21, 1993.
FIELD OF THE INVENTION
The present invention is concerned with a process for the production of
pharmaceutical compositions with retarded liberation of active materials.
More specifically, a mixture of an active material, and a low and high
melting lipid or lipoid components are introduced by means of an extruder
screw conveyor into a preheated extruder and brought to a temperature
which is at most 4.degree. C. above the melting temperature of the low
melting component at a pressure of 200 to 600 kPa (N/m.sup.2). The mass is
extruded through a nozzle plate with a nozzle diameter of 1.2 to 4 mm and
subsequently cooled and, if desired, granulated.
BACKGROUND
From EP0 043,254 is a known process for the production of pharmaceutical
compositions with a retarded release of active materials which is based
upon a selective melting process of at least two lipid or lipoid
components which have a retarding action for pharmaceutically active
materials mixed with these components. Retarded release, or a more
commonly referred to as sustained release, concerns the timed control of
the liberation of active materials from active-material containing
compositions and especially from pharmaceutical compositions. Retarded
release compositions, therefore, achieve a prolongation of the period of
action and avoid too quick and/or too concentrated a release of the active
materials in the compositions, and too high of peaks of the blood or
tissue levels, which can lead to undesirable side effects.
The process is characterized in that
(a) the active material is finely divided;
(b) the active material in finely divided form is mixed not only with a
finely divided, high melting lipid or lipoid component but also with a
finely divided, low melting lipid or lipoid component, the weight ratio of
the two lipid or lipoid components thereby being in the range of from 1:5
to 5:1;
(c) the resulting mixture of active material and lipid or lipoid components
is brought to a temperature which lies above the melting point of the low
melting component but below the melting point of the high melting
component, the active material and the high melting lipid or lipoid
component thereby being uniformly dispersed in the molten low melting
lipid or lipoid component;
(d) after the melting of the low melting component, the resulting mixture
is allowed to cool below the melting point thereof; and
(e) during the cooling or thereafter, the resulting mixture is granulated,
the statements "low melting" and "high melting" thereby being used with
reference to the relationship to one another without including any
particular melting points.
Although it has already proved to be technically useful, the said process
has certain disadvantages which, in particular, impede a continuous and
automatically controlled production process. Thus, hitherto, it has not
been possible to carry out the melting process continuously. In the Patent
Specification, it is admittedly suggested, inter alia, to bring about the
melting of the low melting component solely by means of the frictional
heat of an extruder and, in this way, to omit a separate heating of the
mixture. However, experiments recently carried out have shown that the
frictional heat of an extrusion process is not sufficient completely to
melt the low melting component. Therefore, the extrudate obtained is
inhomogeneous and cannot be used for the granulation or other working up
to give a medicament. Consequently, hitherto it has not been possible
homogeneously to extrude the partly melted product. If, now, an attempt is
made to increase the frictional heat by increasing the speed of rotation
of the screw conveyor, then, without the working temperature increasing
substantially, surprisingly a demixing takes place and, due to an extreme
pressure increase in front of the nozzle plate, the extruder is sometimes
stressed as far as a material destruction (breakage of the screw conveyor)
without it having been possible to achieve the desired effect.
Consequently, according to EP0 043,254, as previously, each batch must
itself be mixed in appropriately dimensioned vessels, heated and again
cooled within a previously determined period of time scheme. This is not
only time-consuming but is automatically involved with many empty runs for
cleaning and resupplying between the actual production batches. According
to the previous production process in a 114 kg capacity planet mixer, the
heating up time up to the melting range of 58.degree. to 60.degree. C.
itself amounted, for example, to 1 hour. Furthermore, the material loss,
i.e. the loss of active and adjuvant materials which remain adhering to
the walls of the vessel and which, as a rule, are lost in the course of
the cleaning process, is far from negligible. A further disadvantage of
the process is that, after completion of the melting process, the final
mixture is obtained in large lumps or as a melt cake which must first be
removed from the melting vessel by manual shovelling and must then be
comminuted before the final retarded mixture can be transferred to a
granulator.
However, attempts to use an extruder with additional heating also initially
failed completely. Even with the supply of heat, it was, namely, first not
possible to produce an extrudate. Starting from the obvious assumption
that the very short residence time of 2 to 5 minutes of the mixture in the
extruder required a high melting temperature, as melting temperature there
was chosen a temperature range lying only slightly below the melting point
of the high melting component. As was to have been expected, the low
melting component was thereby melted but, at the same time, an unexpected
squeezing effect occurred which resulted in the low melting component
being separated from the remainder of the mixture and being pressed in
molten form through the nozzle plate. The mixture remaining in the
extruder was thus separated from the "lubricant" and solidified. The
frictional resistance thereby increased to such an extent that the
extruder was stopped. Attempts to overcome this problem by a variation of
the speed of rotation of the screw conveyor or by reducing the diameter of
the nozzle were unsuccessful. A reduction of the temperature was not
carried out since, due to this means, only a further impairment of the
results was to have been expected. In the case of this consideration, it
was, in particular, taken into account that a lower melting temperature
would automatically undesirable prolong the period of residence of the
mixture in the extruder but the deleterious squeezing out effect can,
therefore, thereby not be favorably influenced because, upon reaching the
nozzle plate, the whole of the low melting component must be present in a
molten state and, consequently, under the pressure of from 200 to 600 kPA
(N/m.sup.2) prevailing in the extruder, would be squeezed off just as in
the case of higher temperatures. Any kind of temperature influence on the
squeezing off effect was not to have been expected. Furthermore, it was to
have been expected that slow heating up and, consequently, low
temperatures in the heating up phase would not only reduce the throughput
but would also require a very long compression path and thus expensive
apparatus.
It is an object of the present invention to overcome the above-mentioned
disadvantages and to provide a fully automatic and continuously operating
melting process according to EP-PS 0 043 254.
SUMMARY
Surprisingly, we have now found that, contrary to expectations and hitherto
inexplicably, the harmful squeezing out effect in the case of a simple
reduction of the working temperature into the lowest possible range
disappears completely and that, consequently, the mixture known from and
suggested in EP0 043,254, in spite of the many previously unsuccessful
attempts, can, without special change of the composition and especially
without any additions for the modification of the friction, be extruded to
give extrudates which are outstandingly suitable for further working up
when the well comminuted and pre-mixed powdered mass is subjected to an
extrusion process at a temperature which lies at most about 4.degree. C.
above the melting temperature of the low melting lipid or lipoid component
at a pressure of about 200 to about 600 kPa (N/m.sup.2) and the partly
melted and well mixed mass according to EP0 043,254 is extruded through a
nozzle plate with a nozzle diameter of about 1.2 to about 4 mm.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a cross-sectional elevation view of an extruder.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, the temperature in the extruder is to
be not more than about 1.degree. to about 4.degree., preferably about
1.degree. to about 3.degree. and most preferably only about 1.degree. to
about 2.degree. C. above the melting temperature of the low melting
component. Thus, the temperature of the heating mantle used must be
correspondingly so adjusted that these temperature ranges are maintained
in the mixture to be worked up over the whole length of the screw
conveyor. Only shortly before passing the nozzle can the temperature be
lowered to the region of the temperature of solidification of the low
melting component when, by means of a sufficient speed of conveying, care
is taken that this component can solidify only after passing the nozzle
plate.
However, even when the temperature lies in the above-given optimum range, a
usable, i.e. granulatable product which can be converted into a
pharmaceutical is only obtained when, at the same time, the diameter of
the nozzles is adjusted to a size adapted to the process. If the nozzle
diameter is less than about 1 mm, then the nozzle plate becomes blocked up
and the extruder is stopped by the increasing friction, which can result
in considerable damage to the machine. If, on the other hand, the diameter
is too great, i.e. greater than about 4 mm, then a product is obtained
which admittedly appears to be usable but which, in actuality, is only
melted on the surface. There is, as it were, obtained a tube with a
melted-on wall and a powdered filling. Thus, here, too, it is important to
find the correct diameter range. This is about 1.2 to about 4, preferably
about 1.3 to about 3 and more preferably about 1.5 to about 2 mm.
The speed of rotation of the screw conveyor(s) is, corresponding to the
extruder used and to the mixture to be worked up, to be so adjusted that
the process pressure of about 200 to about 500 kPa (N/m.sup.2) aimed for
is achieved. A typical range of speed of rotation for an extruder with a
screw conveyor length of about 1200 mm is, in the case of a melt pressure
of about 200 to about 600 kPa (N/m.sup.2), from about 50 to about 200 rpm.
In comparison with the process known from the above-mentioned prior art,
the process according to the present invention possesses considerable
advantage. Due to the continuous method of production, the finishing time
for a unit amount can be considerably reduced. For example, for the
production of 450 kg of granulate hitherto 16 working hours were needed.
By means of the process according to the present invention, the same
amount can be produced in only 4 working hours. The actual production time
is thereby reduced by about 50%. The extruder requires less space and
operates very economically. For example, with an extruder with a screw
conveyor length of only 1400 mm, 110 to 130 kg of extrudate can be
produced per hour.
The present invention will now be described in more detail with reference
to the accompanying FIG. 1. The following examples are given for the
purpose of illustrating the present invention, but are not meant in any
way to restrict the effective scope of the invention.
EXAMPLES
From a storage container (1), a previously prepared, finely divided mixture
consisting of:
37.5 kg hydrogenated castor oil, m.p. 80.degree.-85.degree. C.
60.0 kg powdered stearic acid, m.p. 55.degree.-56.degree. C.
90 kg diltiazem hydrochloride
255.5 kg lactose K
1.5 kg magnesium stearate
1.75 kg carboxymethylcellulose
is passed via a dosing screw conveyor (2) to the actual extruder (3). The
extruder (3) is divided up into several temperable sections (a-f) and is
driven by a controllable motor (4). The mixture is conveyed through the
extruder (3) preheated by the heatable mantle (5), at a speed of rotation
of 170-180 r.p.m. The diameter of the screw conveyor is 50 mm. In all
sections, the mantle temperature is 58.degree.-60.degree. C., which
corresponds to a working temperature of 58.degree.-60.degree.. After an
average period of residence of 2 to 4 minutes, the partly melted product
is extruded through a nozzle plate (6). The nozzle plate (6) contains 20
nozzle openings each with an inner diameter of 1.5 to 3 mm. Under the
described conditions, the apparatus conveys 110 to 120 kg of extrudate per
hour. The extrudate is cooled substantially to ambient temperature in the
form of fine, uniform strands on a slowly moving conveyor belt and is
subsequently passed to a granulator (8). The final granulate finally
reaches a collection container (9). In the simplest case, the sections (a)
to (f) are uniformly tempered so that, in the case of passing through the
extrusion process, the same working temperature prevails over the whole of
the length of the screw conveyor (1400 mm). However, it is also possible
initially to work at a somewhat higher temperature and gradually to
decrease this until, possibly in the last section (f), the working
temperature has been reduced almost to the solidification temperature of
the low melting component. In this way, the cooling phase is shortened
somewhat without it resulting in a blockage of the nozzles.
Otherwise, the mixtures described in EP0 043,254 can be used and working up
without alteration.
A batch for the production of 120 mg diltiazem compositions contains, for
example:
96 kg diltiazem hydrochloride
272 kg lactose K
40 kg hydrogenated castor oil
4.8 kg carboxymethylcellulose
65 kg stearic acid
1.6 kg magnesium stearate.
A batch for the production of 120 mg diltiazem compositions contains, for
example:
120 kg diltiazem hydrochloride
215.3 kg lactose K
64 kg stearic acid NF
40 kg hydrogenated castor oil
2.25 kg carboxymethylcellulose
2.25 kg magnesium stearate.
A batch for the production of 180 mg diltiazem compositions contains, for
example:
180 kg diltiazem hydrochloride
144.124 kg lactose K
48 kg hydrogenated castor oil
68.2 kg stearic acid NF
1.124 kg hydroxyethylcellulose
2.3 kg magnesium stearate.
A batch for the production of 240 mg diltiazem compositions contains, for
example:
13.5 kg lactose X
24 kg diltiazem hydrochloride
12 kg hydrogenated castor oil
10 kg stearic acid
0.175 kg hydroxyethylcellulose
0.4 kg magnesium stearate.
A batch for the production of norfenefrine compositions contains, for
example:
58.5 kg norfenefrine hydrochloride
152.1 kg lactose K
5.85 kg titanium dioxide
29.25 kg hydrogenated castor oil
43.876 kg stearic acid NF
2.924 kg carboxymethylcellulose.
A further batch for the production of norfenefrin compositions contains,
for example:
30 kg norfenefrine hydrochloride
166 kg lactose X
6 kg titanium dioxide
30 kg hydrogenated castor oil
44 kg stearic acid NF
4 kg carboxymethylcellulose.
While there have been described what are presently believed to be the
preferred embodiments of the invention, those skilled in the art will
realize that changes and modifications may be made thereto without
departing from the spirit of the invention, and it is intended to claim
all such changes and modifications as fall within the true scope of the
invention.
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